In anesthesia, neuromuscular blocking agents are used to provide skeletal muscular relaxation during surgery and during intubation of the trachea.
In general there are two types of neuromuscular blocking agents in use, non-depolarizing and depolarizing.
The non-depolarizing agents include d-tubocurarine, pancuronium, gallamine, diallyltoxiferine and toxiferine.
The depolarizing agents include succinylcholine and decamethonium. All of the conventional non-depolarizing agents when used for producing skeletal muscle relaxation in surgery have a long duration of action, e.g. 60 to 180 minutes in man. The depolarizing agents, on the other hand, provide muscle relaxation with duration of action shorter than that of the non-depolarizing agents.
For example, succinylcholine provides a short duration of action of about 5 to 15 minutes whereas decamethonium provides about 20 to 40 minutes duration of muscle relaxation in man.
The long duration of action of non-depolarizing agents is unacceptable in many surgical procedures which take less than one hour because the patient is not generally fully recovered from their effects e.g., the patient may be unable to breathe adequately on his or her own.
Each non-depolarizing agent has inherent side effects. For example, gallamine and pancuronium may cause tachycardia, and d-tubocurarine and diallyltoxiferine may cause hypotension.
While these drugs can be pharmacologically antagonized with anticholinesterase agents, this obviously necesssitates the administration of a second drug which itself may have its own side effects, e.g., bradycardia, gut spasm and bronchorrhea. Thus, to overcome the aforementioned side effects of the anticholinesterase agents, a third drug, an anticholinergic drug, e.g. atropine must also be given.
The depolarizing agents to the best of applicants' knowledge have no pharmacologic antagonists. While in most cases there is no need to reverse the effects of the depolarizing agents, in certain patients the effects of succinylcholine are much prolonged because of abnormal metabolism of the agent by the patient.
The depolarizing agents due to that mode of action which initially causes skeletal muscle contraction and stimulation of smooth muscles are also known to cause the following side effects in certain instances: increased intraocular, and intragastric tension, cardiac arrhythmias, potassium release, and muscle pain.
These side effects caused by the depolarizing agents are not caused by the non-depolarizing agents. It is, therefore, clearly evident that a new neuromuscular blocking agent is needed which would combine the short duration of action of the depolarizing agents with the relatively few side effects and the reversibility of the non-depolarizing agents.
It should be understood that while non-depolarizing agents generally have few side effects, gallamine and pancuronium may cause tachycardia and d-tubocurarine and diallyltoxiferine may cause hypotension.
Surprisingly, the compounds of the present invention appear to be free of these side effects at the dosages anticipated being used clinically in tests made to date. Reference may be made to the text:
The Pharmacological Basis of Therapeutics-Fifth Edition, edited by Louis S. Goodman and Alfred Gilman published by The McMillian Co., copyright 1975, Chapter 28, author George B. Koelle, for further description of neuromuscular blocking agents.
Reference should also be made to the following articles:
Neuromuscular Blocking Activity of a New Series of Quaternary N-Substituted Choline Esters--British Journal of Pharmacology, September, 1971, vol, 43, No. 1, p. 107.
The Pharmacology of New Short Acting Non-depolarizing Ester Neuromuscular Blocking Agents: Clinical Implications--published in Anaesthesia and Analgesia . . . Current Researches, Vol. 52, No. 6, p. 982, November-December, 1973.
Potential Clinical Uses of Short-Acting Non-depolarizing Neuromuscular-Blocking Agents as Predicted from Animal Experiments--published in Anaesthesia and Analgesia . . . Current Researches, Vol. 54, No. 5, p. 669, September-October, 1974; and
U.S. Pat. No. 3,491,099, for a further description of neuromuscular blocking agents.
British Pat. No. 3004031 granted Oct. 10, 1961 discloses a group of substituted laudanosinium salts having neuromuscular blocking activity with non-depolarizing properties.
Belgium Pat. No. 869,415 granted Jan. 31, 1979 discloses a group of substituted tetrahydroisoquinolinium salts having neuromuscular blocking activity, with non-depolarizing properties and a short duration of action. Spanish Patent of Invention No. 477.257 granted Apr. 25, 1979 [notice published in Spanish Official Gazette of Aug. 1, 1979] discloses a second group of substituted tetrahydroisoquinolinium salts having neuromuscular blocking activity, with non-depolarizing properties and an intermediate duration of action. The compounds disclosed in the above-mentioned patents comprise various mixtures of cis and trans isomers of undefined compositions.
The four asymmetric centers present in each compound in all the above mentioned patents allow for sixteen possible stereoisomers. However, only ten stereoisomers can exist due to the symmetry of the molecular structure; for dl pairs (one all trans, one all cis, two cis, trans) and two meso forms (one all cis, one all trans). It is now recognized that the route of synthesis as well as the actual experimental conditions determines the cis/trans ratio and the stereoisomeric ratio. None of the issued patents addresses the question of the stereoisomers, hence they do not teach or even suggest ways for separating the different isomers. Moreover, the above mentioned patents do not teach or suggest that different potencies, durations of action or side effects would exist for the different isomers in the mixtures.
We have discovered a way of providing the all trans (one dl pair, one meso form) and the all cis (one dl pair, one meso form) compounds. These diastereomers exhibit different neuromuscular blocking activities in their potencies and/or durations of action. In the cat, the all trans compounds showed superior potencies, three to six times that of the corresponding all cis compound and a shorter duration of action. In the monkey, the difference in potencies was not as evident, but the durations of action of the all trans compounds were markedly shorter (2-3 times) of those of the all cis compounds. The unexpected differences in duration were explained by measuring the hydrolysis rates by acetylcholinesterase in vitro. The rates of hydrolysis of the cis compounds were very slow compared to that of the corresponding trans form.
Accordingly, this invention provides new neuromuscular blocking agents (sometimes called muscle relaxants) of the formula (I): ##STR3## where B and C are each a group of formula (II) and are meta or para to one another: ##STR4## wherein D is CH.sub.2 CH.sub.2 or CH.dbd.CH (preferably trans); Y is alkyl of 1-4 carbon atoms (methyl, ethyl, propyl or butyl); E and F are H or OCH.sub.3 ; X.sup.- is an anion, preferably pharmaceutically acceptable; and the substituted benzyl and substituted propyl groups are in a trans relationship relative to each other in the nitrogen-containing ring.
Preferred compounds are those wherein Y is methyl.
Compounds having particularly good potency combined with a short duration of action are bis{3-[trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-1-(3,4,5-trimethoxy benzyl)isoquinolinium]propyl}1,3-phenylenedipropionate salts, particularly as the dichloride, diiodide or ditosylate salts.
Compounds having particularly good potency combined with an intermediate duration of action are bis{3-[trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-1-(3,4,5-trimethoxy benzyl)isoquinolinium]propyl}1,4-phenylene-(E,E)-diacrylate and bis{3-[trans-1,2,3,4-tetrahydro-6,7-dimethoxy-N-methyl-1-(3,4,5-trimethoxy benzyl)isoquinolinium]propyl}1,3-phenylene-(E,E)-diacrylate salts, particularly as the dichloride, diiodide or dimesylate salts.
Since the activity of the compounds of the invention resides in the dication, the nature of the anion X.sup.- is relatively unimportant. Suitable pharmaceutically acceptable anions include iodide, mesylate, tosylate, bromide, chloride, sulphate, phosphate, hydrogen phosphate, acetate, benzenesulphonate, succinate, maleate, naphthalenesulphonate and propionate.
It will be appreciated that the compounds of the invention exist as an approximately 1:1 mixture of the racemic (dl) pair and the meso-isomer. This invention further provides means for obtaining the compounds of formula (I) when in the form of one of the aforesaid isomers substantially free of the other isomers, and mixtures of one of the isomers with one or both of the other isomers.
It is preferred that the compounds of the invention be provided in a form where the ratio of the trans, trans compound of the invention to the total of any corresponding cis, cis and cis, trans compounds present as impurities is at least 96:4.
The compounds of formula (I) are used as neuromuscular blocking agents in conjunction with surgery or for intubation of the trachea by conventional parenteral administration, e.g. intramuscular or intravenous administration in solution. The compounds of the present invention shown in formula (I) are administered to patients such as monkeys and man (humans) and other mammals to achieve a neuromuscular block. The dosage for each type of patient will vary because of the peculiarities of the species. However, a suitable intravenous amount or dosage of the compounds of formula (I) to obtain paralyses for monkeys and humans suitable for surgery would be 0.05 to 1.5 mg/kg of body weight, and most preferably 0.1 to 1.0 mg/kg of body weight, the above being based on the weight of the dication which is the active ingredient.
The dosage for intramuscular administration is two to four times the intravenous dose. The compounds of this invention would normally be readministered about every 5 to 45 minutes, depending on whether the activity of the compound is of short or intermediate duration, preferably every 5 to 30 minutes, after initial administration or given as a continuous infusion depending upon the length of time a muscular block is desired, and as determined by the anaesthetists and surgeon in charge of the patient. The compounds of this invention are reversible using conventional anticholinesterase agents such as neostigmine and edrophonium and appear to avoid the side effects associated with the depolarizing agents.
The compounds of formula (I) are therefore useful for producing a short or intermediate duration neuromuscular blockade, and the present invention provides a method of producing such blockade in mammals, e.g. man, or monkeys, by intravenously injecting a dose of 0.05 to 1.5 mg/kg to the mammal.
The compounds may be presented in a pharmaceutical formulation for parenteral administration. The formulation may be an aqueous or non-aqueous solution or emulsion in a pharmaceutically acceptable liquid or mixture of liquids, which may contain bacteriostatic agents, antioxidants, buffers, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such formulations are normally presented in unit dosage forms such as ampoules or disposable injection devices, or in multidose forms such as a bottle from which the appropriate dose may be withdrawn, all such formulations sterile.
The compounds of this invention may be presented as a powder, e.g. as a unit dose in a sealed vial to which sterile water or other pharmaceutically acceptable sterile liquid vehicle may be added, preferably by aseptic techniques.
A suitable unit dose to obtain a neuromuscular block for mammals, e.g. humans or monkeys is about 1.0 mg to 300 mg and most preferably 5.0 to 200 mg.
The compounds of this invention if desired may be administered in conjunction with other non-depolarizing agents such as listed above.
Thus a suitable pharmaceutical parenteral preparation for administration to human will preferably contain 1.0 to 300 mg of the compounds of formula (I) of this invention in solution.
A simple and preferred formulation is a solution of the compound of formula (I) in water which may be prepared by simply dissolving the compound into previously sterilized pure water, i.e. pyrogen free water under aseptic conditions and sterilizing the solution.
The compound of formula (I) may also be administered as an infusion of a dextrose solution or a saline solution, e.g. Ringers' solution.
The compounds may also be administered in other solvents such as alcohol, polyethylene glycol and dimethylsulphoxide. They may also be administered intramuscularly as a suspension.
The compounds of this invention provide the same percentage neuromuscular block at unexpectedly lower doses than the previously described cis/trans mixtures. Consequently, the possibility of side effects such as abnormal lowering of blood pressure, histamine release, tachycardia, etc. is substantially reduced. Furthermore, our invention provides means to prepare mixtures of specified isomeric composition.
The compounds of formula (I) may be prepared by the following methods, using a substituted tetrahydroisoquinolinium salt having the trans configuration as previously defined.